Cardiac amyloidosis—An underdiagnosed cause of heart failure: A case report and review of literature

Abstract

Restrictive cardiomyopathy secondary to cardiac amyloidosis is an underdiagnosed, but treatable, cause of heart failure involving an extracellular deposition of misfolded protein. Hereby, we report a case of a female patient with history of nephrotic syndrome for 1 year who subsequently presented with symptoms of heart failure. The findings on cardiac imaging supported the suspicion of cardiac amyloidosis. Further laboratory workup for amyloidosis was pursued along with endomyocardial biopsy which confirmed amyloidosis‐AL type. Patient was started on chemotherapy. The case underscores the importance of a timely diagnosis with the help of symptomatology and imaging along with a multidisciplinary approach for patient care.

Cardiac amyloidosis should be considered in patients with diastolic heart failure and nephrotic syndrome. Strain analysis is a specific finding. A high index of suspicion is required and early initiation of therapy improves outcomes.

1. BACKGROUND

Restrictive cardiomyopathy secondary to amyloidosis is associated with significant morbidity and mortality. Twelve types of cardiac amyloidosis have been described ¹ , ² ; however, transthyretin (ATTR) and immunoglobulin light‐chain (AL) cardiac amyloidosis comprise roughly 98% of cases. ³ Transthyretin, a hepatic protein that transports thyroid hormone and retinol, can dissociate, misfold, and aggregate into insoluble amyloid fibrils. Wild‐type ATTR cardiac amyloidosis is more prevalent in the elderly with a characteristically male predominance, while variant ATTR, which results from autosomal dominant transthyretin gene mutation, can be encountered from the 3rd to 8th decades. ³

Here, we describe a case of a middle‐aged female with 1‐year history of nephrotic syndrome who subsequently presents with symptoms of heart failure. We further discuss disease pathogenesis and management options.

2. CLINICAL PRESENTATION

A 58‐year‐old female patient with hyperlipidemia, hypothyroidism, and proteinuria presented with a one‐year history of leg swelling and dyspnea on exertion. Physical examination was remarkable for jugular venous distension, positive Kussmaul sign, and bilateral pitting edema. Laboratory workup showed hypoalbuminemia, hypercholesterolemia, elevated brain natriuretic peptide (BNP), and urine 24‐h protein of 2.375 g. Electrocardiogram (EKG) showed low QRS voltage and left atrial enlargement (Figure 1). A transthoracic echocardiogram (TTE) showed borderline concentric left ventricular hypertrophy, biatrial enlargement, grade III diastolic dysfunction (Figures 2A–C and 3A). Global longitudinal strain (GLS) was −9.3% with relative apical sparing (Figure 3B). Due to these findings, we proceeded with testing for amyloid cardiomyopathy.

FIGURE 1.

Electrocardiogram (EKG) showing low QRS voltage and left atrial enlargement

FIGURE 2.

Mitral inflow and tissue Doppler echocardiography showing grade III diastolic dysfunction. (A) E/A of 1.7 with deceleration time of 158 ms. (B,C) Decreased both septal and lateral e′ velocities with elevated E/e′.

FIGURE 3.

(A) Transthoracic echocardiogram showing left ventricular hypertrophy, biatrial enlargement. (B) Global longitudinal strain (GLS) with relative apical sparing. (C) Pyrophosphate (PYP) scan with the heart‐to‐contralateral uptake ratio of 1.5.

Pyrophosphate (PYP) scan was equivocal with the heart‐to‐contralateral uptake ratio of 1.51 (Figure 3C). Urine protein electrophoresis (UPEP) showed monoclonal spike in the beta region with estimated concentration of 1.226 g/24‐h. Serum protein electrophoresis (SPEP) showed beta‐2 globulins appear increased relative to beta‐1globulins. Evaluation revealed one restricted band migrating in the alpha‐2 region. Estimated concentration is 1.2 g/dl. Free kappa/lambda light‐chain ratio was 0.15. Immunofixation did not reveal any monoclonal protein. Serum immunofixation did not reveal any monoclonal protein. Urine immunofixation showed one free lambda monoclonal protein migrating in the beta region.

With the above findings, a decision was made to perform an endomyocardial biopsy (EMB). This showed deposition of amorphous, extracellular, eosinophilic material within the interstitium and endocardium. Staining with Congo red revealed green‐birefringence when viewed in cross‐polarized light, consistent with a diagnosis of amyloidosis (Figure 4A,B). Congophilic deposits were microdissected and underwent mass spectrometry‐based proteomics, which revealed a peptide profile consistent with AL (lambda)‐type amyloid deposition. Genetic sequencing was performed, and no variants were identified. After discussing with a hematologist, she was commenced on a chemotherapy regimen with cyclophosphamide, bortezomib, and dexamethasone (CyBorD) with Daratumumab. Bone marrow biopsy was done after third cycle of chemotherapy and showed normocellular marrow with active hematopoiesis. A diuretic and angiotensin‐converting enzyme inhibitor were also started. Symptomatic improvement was noted on follow‐up appointment.

FIGURE 4.

AL (lambda)‐type myocardial amyloid deposition. The endomyocardial biopsy shows extracellular amorphous material (arrow) (A; hematoxylin and eosin stain). Congo red histochemistry demonstrates green‐birefringence under cross‐polarized light, confirming a diagnosis of amyloidosis (arrowheads) (B) (both, 200× original magnification).

3. DISCUSSION

AL amyloidosis is considered a toxic infiltrative cardiomyopathy due to its cytotoxic effects causing both apoptosis and necrosis. ⁴ The incidence of AL amyloidosis, although hard to calculate, is estimated to be ~0·8/100,000 population and the cause of death in ~1 per 1500 deaths in the UK. ⁵ Direct cardiotoxicity is mediated by an activation of p38 mitogen‐activated protein kinase (MAPK) pathway with subsequent oxidative stress and cardiomyocyte death. ⁶ Natriuretic peptide type‐B (BNP) and N‐terminal pro‐BNP (NT‐pro‐BNP) are also upregulated as a consequence of the activated MAPK pathway and elevated filling pressures; therefore, they are proven to be strong prognostic determinants of AL cardiac amyloidosis. ⁶ AL amyloidosis often manifests with multiorgan involvement including the kidneys and nervous system. ⁷ Kidneys are usually affected resulting in nephrotic syndrome as seen in our patient. ⁷ An effort to determine the specific type of precursor amyloid protein is essential because of variable clinical courses and treatment strategies.

AL amyloidosis is usually associated with a hematological disorder, including plasma cell dyscrasias or B‐cell lymphoma. Multiple myeloma (MM) results from an unregulated proliferation of plasma cells, thereby overproducing clonal light‐chains. ⁷ Typical manifestations include anemia, hypercalcemia, renal dysfunction, and bone pain. Approximately 5%–10% of patients with AL amyloidosis have overt MM and a similar proportion of MM patients have an evidence of AL amyloidosis. ⁷ To diagnose AL amyloidosis, both SPEP and UPEP with immunofixation, together with serum‐free light‐chain quantification, must be obtained. Pathological confirmation with biopsy of affected organs should be considered to establish the definite diagnosis. ⁸ It is worth noting that the presence of monoclonal gammopathy does not equate to, and is not diagnostic of, AL amyloidosis. Rather, monoclonal gammopathy is common and can be seen in up to 40% of those with ATTR cardiac amyloidosis. ³ Our patient had monoclonal protein spike, thus raising suspicion for plasma cell dyscrasia. AL cardiac amyloidosis was then confirmed with biopsy.

Clinical manifestations of AL amyloidosis are often non‐specific including fatigue, weight loss, and poor appetite. Macroglossia and periorbital bruising are relatively specific, but insensitive, to AL amyloidosis. ⁹ One of the early manifestations of cardiac amyloidosis is dyspnea on exertion attributed to rigid, noncompliant ventricles as well as atrial stiffness. Based on the RHC, prominent v‐wave may be seen in the pulmonary capillary wedge tracings in the absence of significant mitral regurgitation. Other findings include rapid y descent, dip and plateau sign.

Strain analysis showing relative apical sparing with a “cherry on top” appearance seems to be the most sensitive and specific finding of amyloidosis. ¹⁰ Amyloid deposition serves as an arrhythmogenic substrate and predisposes to atrial fibrillation; therefore, thromboembolic complication can also be an initial presentation. ¹⁰

The efficacy of treatment mainly relies on how early the condition can be recognized, with remission rates of 40%–60%. ¹⁰ Timely diagnosis and initiation of treatment are associated with better outcomes with survival ranging from 79%, if diagnosed during the first 6 months, to 19% after 19 months. ¹¹ Diuretics are the mainstay management for heart failure. Chemotherapy that targets the underlying plasma cell dyscrasia has changed considerably in the past decade, resulting in markedly improved response rates and prolonged survival.

4. CONCLUSION

Cardiac amyloidosis‐related symptoms may be an initial presentation of underlying plasma cell dyscrasias. A high index of suspicion is required for prompt diagnosis and early initiation of treatment to improve survival outcomes. Endomyocardial biopsy should be performed when a diagnosis is unclear as treatment strategies for AL and ATTR cardiac amyloidosis differ markedly.

AUTHOR CONTRIBUTIONS

Drafting of the manuscript: KP, JB. Tables and formatting: KP, PS, PH, JB. Concept and design: KP, JB, GDRP, EAS. Acquisition, analysis, or interpretation of data: KP, JB. Critical revision of the manuscript for important intellectual content: EAS. Supervision: PS, EAS.

FUNDING INFORMATION

No funding is required for this manuscript.

CONFLICT OF INTEREST

The authors declare that they have no competing interests.

CONSENT

Written informed consent was obtained from the patient to publish this report in accordance with the journal's patient consent policy.

Parmar K, Benjanuwattra J, Sethi P, et al. Cardiac amyloidosis—An underdiagnosed cause of heart failure: A case report and review of literature. Clin Case Rep. 2022;10:e06525. doi: 10.1002/ccr3.6525

DATA AVAILABILITY STATEMENTS

Not applicable.